The present relates to new dipeptide compounds capable of controlling phytopathogens which cause considerable economic damage to agricultural crops.
More specifically, the present invention relates to new dipeptide compounds capable of effectively controlling phytopathogens of crops of great economic interest, such as, for example, vines, potatoes and tobacco, as well as their agronomic use, alone or mixed with one or more active principles with a fungicidal activity, and the process for their preparation.
The patent application EP 652 229 A2 discloses suitably functionalized oligopeptide compounds having a high fungicidal activity consisting of one or two aliphatic amino acids, such as valine, leucine and isoleucine, conjugated to one or two aromatic amino acids, such as phenyl-glycine, phenylalanine and xcex2-phenylalanine (or 3-amino-3-phenylpropanoic acid), whose free amine and carboxyl functions can also be suitably functionalized.
Patent application EP 718 280 A2 again describes compounds based on 3-amino-3-arylpropanoic acids suitably substituted. Among the compounds based on 3-amino-3-arylpropanoic acids claimed, there are also dipeptide compounds obtained by means of bonds between the amine group of said 3-amino-3-arylpropanoic acids and the carboxyl group of an amino acid, such as valine appropriately functionalized on its amine function.
Said patent applications EP 652 229 A2 and EP 718 280 A2, among the numerous examples which illustrate the invention, describe dipeptlde compounds, whose basic skeleton consists of L-valine conjugated by means of its carboxyl group with an aromatic xcex2-amino acid (3-amino-3-aryl-propanoic acid) and whose structures can be defined by a single general formula (Ia): 
wherein:
R1 represents a linear or branched C1-C8 alkyl group, or a phenyl group;
R2 represents a linear or branched C1-C8 alkyl group;
R3 can be a phenyl group optionally substituted.
On the basis of what is described in the above patent applications, these dipeptide compounds are particularly effective in the control of Oomycetes.
The products specified which can be defined by this general formula are generally characterized by the functionalization of the amine residue with a carboxy-tertbutyl group (R1 therefore means tert-butyl) or by the esterification of the carboxyl residue with an alkyl group, and the R2 group therefore has the meaning of a methyl, ethyl and isopropyl group, in the presence of an R3 phenyl group.
The compounds having general formula Ia also allow synergic fungicidal mixtures to be obtained with the levorotatory isomer of methyl (N-phenylacetyl-N-2,6-xylyl)alaninate (Benalaxyl), as described in the patent WO 98 26654 A2.
The Applicant has now found that new dipeptide compounds having formula (I), which have never been described before, have a higher fungicidal activity than those of the dipeptide compounds specified in the known art.
The present invention therefore relates to dipeptide compounds having formula (I): 
wherein:
R1 represents an isopropyl or phenyl group;
R2 represents a methyl group;
R3 can be a phenyl group substituted in position 4 with an R4 group; or it can represent a 2-benzothiazole group, optionally substituted with an R5 group;
R4 and R5 can be a fluorine or chlorine atom; a methyl or ethyl group; or a methoxyl group; or they can represent a cyano group.
The configuration of the atom of the valine residue present in all compounds having formula (I) is S, according to the Cahn, Ingold and Prelog convention.
The absolute configuration of the chiral atom of aromatic xcex2-amino acid incorporated in the dipeptide compound may, on the contrary, be either S or R.
The compounds of the present invention, considering jointly the asymmetrical centres present in the molecule, may be in diastereoisomeric forms Sxe2x80x94S or Sxe2x80x94R, wherein the first letter refers to the chiral centre of valine whereas the second letter describes the chiral centre of aromatic xcex2-amino acid, or they can be present as a diastereoisomeric mixture in which the two forms are in any molar ratio.
The Applicant has found that compounds in which the absolute configuration of the chiral atom of aromatic xcex2-amino acid incorporated in the dipeptide compound is R, have a greater fungicidal activity.
A particular aspect of the present invention therefore relates to dipeptide compounds having formula (I) wherein the absolute configuration of the chiral atom of the xcex2-amino acid residue is R, as represented by general formula (II) 
wherein:
R1, R2, R3 have the meaning defined above (formula I).
The compounds of the present invention can be conveniently used in agriculture as a diastereoisomeric mixture in which the two forms can be present in any molar ratio.
According to present conventions, a compound having formula (I) with an epimeric form Sxe2x80x94RS contains these diastereoisomeric forms Sxe2x80x94S and Sxe2x80x94R in an equimolecular ratio.
Owing to the higher activity of compounds in which the absolute configuration of the chiral atom of aromatic xcex2-amino acid is R, the compounds having formula (I) are preferably used as a diastereoisomeric mixture in which the diastereoisomeric form Sxe2x80x94R is greater than 80%.
Even more preferable are diastereoisomeric mixtures in which the diastereoisomeric form Sxe2x80x94R is present in greater quantities, such as, for example, diastereoisomeric mixtures containing the form Sxe2x80x94R in quantities exceeding 90%, 95% or 98%.
The use of compounds having formula (I) in the sole dlastereoisomeric form Sxe2x80x94R, is the most preferable.
The compounds having formula (I) can be used alone or optionally associated with at least one other compound having a fungicidal activity.
The present invention therefore relates to fungicidal compositions comprising:
a) a dipeptide compound having formula (I) as a diastereoisomeric mixture in which the two forms can be present in any molar ratio, or as a sole diasatereoisomeric form Sxe2x80x94R;
b) one or more fungicides selected from:
(1) Cymoxanil corresponding to 1-(2-cyano-2-methoxyimino-acetyl)-3-ethylurea;
(2) Fosetyl-Al corresponding to the aluminum salt of ethyl hydrogen phosphonate;
(3) Potassium phosphonate;
(4) Benalaxyl corresponding to methyl N-(phenyl-acetyl)-N-2,6-xylyl-RS-alaninate;
(5) Methyl N-(phenylacetyl)-N-2,6-xylyl-R-alaninate;
(6) Metalaxyl corresponding to methyl N-(2-methoxyacetyl)-N-2,6-xylyl-RS-alaninate;
(7) Mefenoxam corresponding to methyl N-(2-methoxyacetyl-N-2,6-xylyl-R-alaninate;
(8) Oxadixyl corresponding to 2-methoxy-N-(2-oxo-1,3-oxazolidin-3-yl)acet-2xe2x80x2,6xe2x80x2-xylidinide;
(9) Ofurace corresponding to DL-3-[N-chloroacetyl-N-(2,6-xylyl)-amino]-xcex3-butyrolactone;
(10) Iprovalicarb corresponding to O-(1-methylethyl)-N-[2-methyl-1-[[[1-(4-methylphenyl)ethyl]-amino]carbonyl]propyl]carbamate;
(11) Azoxystrobin corresponding to methyl (E)-2-[2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate;
(12) Kresoxym-methyl corresponding to methyl (E)-methoxyimino-xcex1-[o-tolyloxy)-o-tolyl]acetate;
(13) Metominofen corresponding to the experimental abbreviation SSF-126 and corresponding to N-methyl-(E)-methoxyimino-(2-phenoxyphenyl)acetamide;
(14) Acylbenzolar corresponding to methylbenzothiadiazole-7-thiocarboxylate;
(15) Famoxadone corresponding to 5-methyl-5-(4-phenoxyphenyl)-3-(phenylamino)oxazolidin-2,4-dione;
(16) Fenamidone corresponding to 4-methyl-4-phenyl-1-(phenylamino)-2-methylthioimidazolidin-5-one;
(17) IKF916 corresponding to 2-cyano-4-chloro-5-(4-methylphenyl)-1-(N,N-dimethylaminosulfamoyl)-imidazole;
(18) Fluazinam corresponding to 3-chloro-N-(3-chloro-5-trlfluoromethyl-2-pyridyl)-xcex1,xcex1,xcex1-tri-fluoro-2,6-dinitro-p-toluidine;
(19) Dimethomorph corresponding to (E,Z)-4-[3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)acryloyl]morpholine;
(20) Flumetover corresponding to N,N-diethylamide of 4-trifluoromethyl-6-(3,4-dimethoxyphenyl)benzoic acid;
(21) Chlorothalonil corresponding to 1,3-dicyano-2,4,5,6-tetrachlorobenzene;
(22) Thiram corresponding to bis-(dimethylthiocarbamoyl)disulfide (polymer);
(23) Propineb corresponding to the zinc salt of propylenebis(dithiocarbamate)(polymer);
(24) Mancozeb corresponding to the manganese and zinc salt of ethylenebis(dithiocarbamate) (polymer);
(25) Maneb corresponding to the manganese salt of ethylenebis(dithiocarbamate)(polymer);
(26) Zineb corresponding to the zinc salt of ethylenebis(dithiocarbamate)(polymer);
(27) Dichlofluanide corresponding to N-dichloro-fluoromethylthio-Nxe2x80x2,Nxe2x80x2-dimethyl-N-phenylsulfamide;
(28) Tolylfluanide corresponding to N-dichlorofluoromethylthio-Nxe2x80x2,Nxe2x80x2-dimethyl-N-p-tolylsulfamide;
(29) Captano corresponding to N-(trichloromethylthio)cyclohex-4-ene-1,2-dicarboxyimide;
(30) Folpet corresponding to N-(trichloromethylthio)phthalimide;
(31) Dithianon corresponding to 5,10-dihydro-5,10-dioxonaphthol[2,3-b]-1,4-dithi-in-2,3-dicarbonitrile;
(32) Etridiazole corresponding to ethyl-3-trichloromethyl-1,2,4-thiadiazolyl ether;
(33) Hymexanol corresponding to 5-methylisoxazol-3-ole;
(34) Protiocarb corresponding to S-ethyl-(3-dimethylaminopropyl)thiocarbamate;
(35) Propamocarb corresponding to propyl-(3-dimethylaminopropyl)carbamate;
(36) A copper (I) salt or copper (II) salt, such as copper oxychloride, copper hydroxide, or copper sulfate;
(37) Mepanipyrim corresponding to N-(4-methyl-6-prop-1-inylpyrimidin-2-yl)aniline;
(38) Pirymethanil corresponding to N-(4,6-dimethylpyrimidin-2-yl)aniline;
(39) Cyprodinil corresponding to N-(4-methyl-6-cyclopropylpyrimidin-2-yl)aniline;
(40) R-3-aminobutanoic acid or RS-3-aminobutanoic acid.
The compounds having formula (I) can be obtained by means of numerous synthetic methods.
For merely illustrative but non-limiting purposes, schemes A and B indicate some preparations of compounds having formula (I) wherein R1, R2 and R3 have the meanings already defined in the description of general formula (I). 
The carbamate (III) is reacted with an organic base, such as N-methylmorpholine, triethylamine, or N,N-dimethylbenzylamine, in an organic solvent such as dichloromethane, or ethyl acetate, or toluene, at a temperature ranging from xe2x88x9240xc2x0 C. to 25xc2x0 C. Alkyl chloroformiate (V) is then added, wherein R6 has the meaning of a linear or branched C1-C8 alkyl group, such as for example, methyl, ethyl, isopropyl, isobutyl, the temperature being maintained within a range of xe2x88x9240xc2x0 C. to 25xc2x0 C. The ester (IV), optionally diluted in the reaction solvent, is then added, the temperature being maintained within a range of xe2x88x9240xc2x0 C. to 30xc2x0 C., obtaining the desired compound having formula (I). 
The ester (IV) is reacted with the anhydride (VI), whose preparation is described for example in xe2x80x9cBerichtexe2x80x9d (1906), Vol. 39, page 857 or in xe2x80x9cJournal of Chemical Societyxe2x80x9d (1950), page 3213 and page 3461, in an organic solvent, such as dichloromethane, trichloromethane, ethyl acetate or tetrahydrofuran, in the presence of or without an organic base, such as triethylamine or N-methyl-N,N-dioctylamine, at a temperature ranging from xe2x88x9280xc2x0 C. to room temperature, as described for example in xe2x80x9cJournal of Chemical Societyxe2x80x9d (1950), page 3461. The dipeptide (VII) thus obtained is reacted, for example, in an organic solvent, such as dichloromethane or ethyl acetate, with the chloroformate (VIII) in the presence of an inorganic base, such as sodium bicabonate or potassium carbonate, or in the presence of an organic base, such as triethylamine, pyridine, N-methylmorpholine, N,N-dimethylbenzylamine, at a temperature ranging from xe2x88x9240xc2x0 C. to 30xc2x0 C., to obtain the desired compound having formula (I).
The carbamate (III) can be easily prepared by the addition of an alkylchloroformiate (VIII) to an aqueous solution of L-valine, in the presence of an inorganic base, such as sodium bicarbonate, potassium carbonate or sodium hydroxide, or an organic base such as triethylamine, at a temperature ranging from 0xc2x0 C. to 25xc2x0 C.; or by the addition of chloroformiate (VIII) to a solution of silanized L-valine, prepared xe2x80x9cin situxe2x80x9d using the conditions described, for example, in xe2x80x9cBerichtexe2x80x9d (1967), Vol. 100, page 1638 or in xe2x80x9cBerichtexe2x80x9d (1970), Vol. 103, page 3353.
The racemic ester having formula (IV) can be obtained according to Scheme C below: 
A suitable para-substituted benzaldehyde (IX) is reacted with malonic acid (X) in the presence of an ammonium salt, such as ammonium acetate or ammonium propionate, in a protic solvent, such as methyl alcohol, ethyl alcohol or ethylene glycol, at a temperature ranging from 40xc2x0 C. to the boiling point of the pre-selected solvent, to obtain the desired xcex2-amino acid (XI).
The xcex2-amino acid (XI) thus obtained is transformed into methyl ester (VI) by means of one of the methods known in literature for the esterification of xcex1-amino acids, for example, using solutions of a mineral acid, such as sulfuric acid or hydrochloric acid, or an organic acid, such as methanesulfonic acid or para-toluenesulfonic acid, in methanol, at a temperature ranging from room temperature to the boiling point of the solvent mixture; or by reacting said acid (XI) in methanol in the presence of equimolecular quantities or with an excess of thionyl chloride, at a temperature ranging from 20xc2x0 C. to the boiling point of the solvent mixture.
In order to obtain compounds having formula (I) as a diastaereoisomeric mixture in which one of the diastereoisomeric forms is greater than 50%, an ester having formula (IV), in which one of the enantiomeric forms is greater than 50%, was obtained by the fractional crystallization of the salt formed by the reaction of the racemic ester (IV) with a suitable, optically active acid, such as tartaric acid, camphorsulfonic acid, O-(N-phenylaminocarbonyl)lactic acid, or an N-alkoxycarbonyl-xcex1-amino acid.
Other methods for obtaining an ester having formula (IV) in an optically active form use an enantioselective, enzymatic hydrolysis of the racemic ester (IV) to obtain, depending on the enzyme used, the ester (IV) or acid (XI) in the desired enantiomeric form. The optically active acid (XI) is subsequently transformed into the required ester (IV) in the desired enantiomeric form, by one of the esterification methods already described for transforming the racemic acid (XI) into the racemic ester (IV).
Compound (I) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 148.
Compound (2) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 294.
Compound (3) is easily available on the market.
Compound (4) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 32.
Compound (5) is described in patent application WO 98 26654 A2.
Compound (6) is described in English patent GB 1,500,581.
Compound (7) is described in patent application WO 96 01559 A1.
Compound (8) is described in English patent GB 2,058,059.
Compound (9) is described in xe2x80x9cPhytopatological Newsxe2x80x9d (1978), Vol. 9, page 142.
Compound (10) is described in patent applications EP 610,764 and EP 550,788.
Compound (11) is described in European patent application EP 382,375.
Compound (12) is described in European patent application EP 253,213.
Compound (13) is described in American patent U.S. Pat. No. 5,185,242.
Compound (14) is described in American patent U.S. Pat. No. 4,931,581.
Compound (15) is described in xe2x80x9cBrighton Crop Protection Conferencexe2x80x94Pests and Diseasesxe2x80x9d (1996), Congress Acts.
Compound (16) is described in European patent application EP 629,616.
Compound (17) is described in European patent application EP 705,823.
Compound (18) is described in European patent application EP 31,257.
Compound (19) is described in European patent application EP 219,756.
Compound (20) is described in European patent applications EP 360,701 and EP 611,232.
Compound (21) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 120.
Compound (22) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 534.
Compound (23) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 469.
Compound (24) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 339.
Compound (25) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 340.
Compound (26) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 569.
Compound (27) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 175.
Compound (28) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 537.
Compound (29) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 87.
Compound (30) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 599.
Compound (31) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 225.
Compound (32) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 252.
Compound (33) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 314.
Compound (34) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 473.
Compound (35) is described in xe2x80x9cThe Pesticide Manualxe2x80x9d, 1983, VIIth edition, British Crop Protection Council Ed., page 471.
Compounds (36) are easily available on the market.
Compounds (37), (38) and (39) are described in xe2x80x9cPesticide Sciencexe2x80x9d (1996), Vol. 47, pages 191-197.
Compound (40) is described in patent application WO 95 15684.
The fungicidal compositions comprising these compounds having formula (I) alone or mixed with one or more products (1)-(40), object of the present invention, have a high fungicidal activity with respect to numerous fungine species. Examples of pathogens controlled by the above compositions, and also examples of application crops, are provided hereunder for illustrative purposes only, without there being any limitations whatsoever:
Plasmopara viticola (vines);
Phytophtora infestans (tomatoes, potatoes);
Phytophtora nicotianae (tobacco, ornamental plants);
Phytophtora paimivora (cocoa);
Phytophtora cinnamomi (pineapples, citrus fruit);
Phytophtora capsici (peppers, tomatoes, cucurbitaceae);
Phytophtora cryptogea (tomatoes, plums, ornamental plants);
Phytophtora megasperma (ornamental plants);
Phytophtora citri (citrus fruit);
Peronospora tabacina (tobacco);
Pseudoperonospora cubensis (cabbages, cucurbitaceae);
Pseudoperonospora humili (hops);
Bremia (salad).
The compositions object of the present invention are capable of carrying out a high fungicidal action, allowing preventive, protective, prophylactive, systemic, curative and eradicative treatment to be applied.
The compositions object of the present invention can be used in different quantities depending on the crop, pathogen, environmental conditions and type of formulation adopted.
The application doses per hectare of compound having formula (I) are generally within the range of 5-500 g, whereas those of the possible compounds (1)-(40) present in the composition, are within the range of 5-3500 g.
The compositions object of the present invention can be applied to any part of the plant, for example leaves, stalks, branches and roots, or on the seeds themselves before sowing, or even on the ground where the plant grows.
The compositions object of the present invention are used in agronomic practice as compositions in various forms such as for example: dry powders, wettable powders, emulsifiable concentrates, micro-emulsions, pastes, granulates, solutions, suspensions, etc. The selection of the type of composition depends on the specific use.
The compositions are prepared with known methods, for example by diluting or dissolving the active substance with a solvent medium and/or a solid diluent, optionally in the presence of surface-active agents.
Solid diluents or carriers which can be used are: silica, kaolin, bentonite, talc, fossil flour, dolomite, calcium carbonate, magnesia, chalk, clays, synthetic silicates, attapulgite, sepiolite.
Various solvents, for example aromatics (xylols or mixtures of alkylbenzols), paraffins (petroleum fractions), alcohols (methanol, propanol, butanol, octanol, glycerine), amines, amides (N,N-dimethylformamide, N-methylpyrrolidone), ketones (cyclohexanone, acetone, acetophenone, isophorone, ethylamylketone), esters (isobutyl acetate, methyl esters of fatty acids obtained for example by the trans-esterification of vegetable oils), can be used as liquid diluents, in addition to water naturally.
Surface-active agents which can be used are salts of sodium, calcium, triethanolamine, or triethylamine of alkyl sulfonates, alkylarylsulfonates, polyethoxylated alkylphenols, fatty alcohols condensed with ethylene oxide, polyoxyethylated fatty acids, polyoxyethylated esters of sorbitol, ilgninsulfonates.
The compositions can also contain special additives for particular purposes such as, for example, adhesive agents, such as Arabic rubber, polyvinyl alcohol, polyvinylpyrrolidone.
The concentration of active substances in the above compositions varies from 0.1% to 98%, preferably from 0.5% to 90%.
If desired, it is possible to also add other compatible active principles to the compositions object of the present invention, such as for example, phytoregulators, antibiotics, herbicides, insecticides, fertilizers.
The following examples are provided for illustrative purposes and do not limit the scope of the present invention.